Spiro-lactam nmda receptor modulators and uses thereof

ABSTRACT

Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalPatent Application No. 62/369,453, filed on Aug. 1, 2016; the contentsof which are hereby incorporated by reference herein in their entirety.

BACKGROUND

An N-methyl-d-aspartate (“NMDA”) receptor is a postsynaptic, ionotropicreceptor that is responsive to, inter alia, the excitatory amino acidsglutamate and glycine and the synthetic compound NMDA. The NMDA receptorcontrols the flow of both divalent and monovalent ions into thepostsynaptic neural cell through a receptor associated channel (Fosteret al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol.Sci. 1990, 11:254-260). The NMDA receptor has been implicated duringdevelopment in specifying neuronal architecture and synapticconnectivity, and may be involved in experience-dependent synapticmodifications. In addition, NMDA receptors are also thought to beinvolved in long term potentiation and central nervous system disorders.

The NMDA receptor plays a major role in the synaptic plasticity thatunderlies many higher cognitive functions, such as memory acquisition,retention and learning, as well as in certain cognitive pathways and inthe perception of pain (Collingridge et al., The NMDA Receptor, OxfordUniversity Press, 1994). In addition, certain properties of NMDAreceptors suggest that they may be involved in theinformation-processing in the brain that underlies consciousness itself.

The NMDA receptor has drawn particular interest since it appears to beinvolved in a broad spectrum of CNS disorders. For instance, duringbrain ischemia caused by stroke or traumatic injury, excessive amountsof the excitatory amino acid glutamate are released from damaged oroxygen deprived neurons. This excess glutamate binds to the NMDAreceptors which opens their ligand-gated ion channels; in turn thecalcium influx produces a high level of intracellular calcium whichactivates a biochemical cascade resulting in protein degradation andcell death. This phenomenon, known as excitotoxicity, is also thought tobe responsible for the neurological damage associated with otherdisorders ranging from hypoglycemia and cardiac arrest to epilepsy. Inaddition, there are preliminary reports indicating similar involvementin the chronic neurodegeneration of Huntington's, Parkinson's andParkinson's related conditions such as dyskinesia and L-dopa induceddyskinesia and Alzheimer's diseases.

Activation of the NMDA receptor has been shown to be responsible forpost-stroke convulsions, and, in certain models of epilepsy, activationof the NMDA receptor has been shown to be necessary for the generationof seizures. Neuropsychiatric involvement of the NMDA receptor has alsobeen recognized since blockage of the NMDA receptor Ca⁺⁺ channel by theanimal anesthetic PCP (phencyclidine) produces a psychotic state inhumans similar to schizophrenia (reviewed in Johnson, K. and Jones, S.,1990). Further, NMDA receptors have also been implicated in certaintypes of spatial learning.

The NMDA receptor is believed to consist of several protein chainsembedded in the postsynaptic membrane. The first two types of subunitsdiscovered so far form a large extracellular region, which probablycontains most of the allosteric binding sites, several transmembraneregions looped and folded so as to form a pore or channel, which ispermeable to Ca*, and a carboxyl terminal region. The opening andclosing of the channel is regulated by the binding of various ligands todomains (allosteric sites) of the protein residing on the extracellularsurface. The binding of the ligands is thought to affect aconformational change in the overall structure of the protein which isultimately reflected in the channel opening, partially opening,partially closing, or closing.

A need continues to exist in the art for novel and more specific and/orpotent compounds that are capable of modulating NMDA receptors, andprovide pharmaceutical benefits. In addition, a need continues to existin the medical arts for orally deliverable forms of such compounds.

SUMMARY

The present disclosure includes compounds that can be NMDA modulators.More specifically, the present disclosure provides a compound having theformula:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof,wherein:

-   -   X is NR¹ or CR²R²;    -   Y is NR¹ or CR²R², wherein one of X or Y is NR¹;    -   R¹ is selected from the group consisting of H, C₁-C₆alkyl,        phenyl, —C(O)—C₁-C₆alkyl, and —C(O)—O—C₁-C₆ alkyl;    -   q is 0 or 1;    -   r is 1 or 2;    -   R⁷ is independently selected from the group consisting of H,        —C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, and halogen;    -   R⁹ is independently selected from the group consisting of H,        —C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, and halogen, or R⁷ and R⁹        taken together with the adjacent carbons to which they are        attached form a 3-membered carbocyclic ring which can be        optionally substituted by one or two substituents independently        selected from the group consisting of halogen, hydroxyl,        —C₁-C₃alkyl, —C₁-C₃alkoxy, —C(O)NR^(a)R^(b), and —NR^(a)R^(b);    -   R² is independently selected for each occurrence from the group        consisting of H, C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b)        and halogen;    -   R⁵ is independently selected for each occurrence from the group        consisting of H, C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b)        and halogen;    -   R⁶ represents one or two optional substitutions each on one or        more available ring carbons, and is independently selected for        each occurrence from the group consisting of C₁-C₆alkyl,        —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen;    -   w is 0, 1, or 2;    -   R³ is selected from the group consisting of H, phenyl, C₁-C₆        alkyl, —C(O)R³¹ and —C(O)OR³²;    -   R³¹ and R³² are each independently H, C₁-C₆alkyl,        —C₃-C₆cycloalkyl, and phenyl; and    -   R^(a) and R^(b) are each independently for each occurrence        selected from the group consisting of H, phenyl, and C₁-C₃alkyl,        or R^(a) and R^(h) taken together with the nitrogen to which        they are attached form a 4-6 membered heterocyclic ring;        -   wherein any aforementioned C₁-C₆ alkyl, independently for            each occurrence, can be optionally substituted by one, two            or three substituents each independently selected from            —C(O)NR^(a)R^(b), —NR^(a)R^(b), hydroxyl,            S(O)_(w)—C₁-C₃alkyl, SH, phenyl and halogen, and any            aforementioned phenyl, independently for each occurrence,            can be optionally substituted by one, two or three            substituents each independently selected from            —C(O)—C₁-C₃alkyl, hydroxyl, —C(O)— C₁-C₃alkyl, methyl, CF₃            and halogen.

Also provided herein are pharmaceutically acceptable compositionscomprising a disclosed compound, and a pharmaceutically acceptableexcipient. Such compositions can be suitable for administration to apatient orally, parenterally, topically, intravaginally, intrarectally,sublingually, ocularly, transdermally, or nasally.

In some aspects, compounds described herein bind to NMDA receptorsexpressing certain NR2 subtypes. In some aspects, the compoundsdescribed herein bind to one NR2 subtype and not another.

In another aspect, a method of treating a condition selected from thegroup consisting of autism, anxiety, depression, bipolar disorder,attention deficit disorder, attention deficit hyperactivity disorder(ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, socialwithdrawal, obsessive-compulsive disorder, phobia, post-traumatic stresssyndrome, a behavior disorder, an impulse control disorder, a substanceabuse disorder, a sleep disorder, a memory disorder, a learningdisorder, urinary incontinence, multiple system atrophy, progressivesupra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile Xsyndrome, tuberous sclerosis, olivio-ponto-cerebellar atrophy, Rettsyndrome, cerebral palsy, drug-induced optic neuritis, ischemicretinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia,Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, musclespasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a braintumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cordinjury, peripheral neuropathy, fibromyalgia, acute neuropathic pain, andchronic neuropathic pain, in a patient in need thereof is provided. Suchmethods may comprise administering to the patient a pharmaceuticallyeffective amount of a disclosed compound or pharmaceutically acceptablesalts, stereoisomers, N-oxides, and hydrates thereof.

In some embodiments, a method of the disclosure includes treatingneuropathic pain, wherein the neuropathic pain is selected from thegroup consisting of herpes, HIV, traumatic nerve injury, stroke,post-ischemia, chronic back pain, post-herpetic neuralgia, fibromyalgia,reflex sympathetic dystrophy, complex regional pain syndrome, spinalcord injury, sciatica, phantom limb pain, diabetic neuropathy, andcancer chemotherapeutic-induced neuropathic pain.

In some embodiments, a method of the disclosure includes treatingdepression. For example, depression may include one or more of majordepressive disorder, dysthymic disorder, psychotic depression,postpartum depression, seasonal affective disorder, bipolar disorder,mood disorder, or depression caused by a chronic medical condition. Incertain embodiments, a disclosed method may treat schizophrenia. Suchschizophrenia may be, for example, paranoid type schizophrenia,disorganized type schizophrenia, catatonic type schizophrenia,undifferentiated type schizophrenia, residual type schizophrenia,post-schizophrenic depression, or simple schizophrenia.

DETAILED DESCRIPTION

This disclosure is generally directed to compounds that are capable ofmodulating NMDA receptors, for example, NMDA receptor antagonists,agonists, or partial agonists, and compositions and/or methods of usingthe disclosed compounds. It should be appreciated that the disclosedcompounds may modulate other protein targets and/or specific NMDAreceptor subtype.

The term “alkyl,” as used herein, refers to a saturated straight-chainor branched hydrocarbon, such as a straight-chain or branched group of1-6, 1-4, or 1-3 carbon atoms, referred to herein as C₁-C₆ alkyl, C₁-C₄alkyl, and C₁-C₃ alkyl, respectively. For example, “C₁-C₆ alkyl” refersto a straight-chain or branched saturated hydrocarbon containing 1-6carbon atoms. Examples of a C₁-C₆ alkyl group include, but are notlimited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl,isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl. In anotherexample, “C₁-C₄ alkyl” refers to a straight-chain or branched saturatedhydrocarbon containing 1-4 carbon atoms. Examples of a C₁-C₄ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl,isopropyl, isobutyl, sec-butyl and tert-butyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.

The term “alkoxy,” as used herein, refers to an alkyl group attached toan oxygen atom (alkyl-O—). Alkoxy groups can have 1-6 or 2-6 carbonatoms and are referred to herein as C₁-C₆ alkoxy and C₂-C₆ alkoxy,respectively. Exemplary alkoxy groups include, but are not limited to,methoxy, ethoxy, propyloxy, isopropoxy, and tert-butoxy.

The term “carbonyl,” as used herein, refers to the radical —C(O)— orC═O.

The term “cyano,” as used herein, refers to the radical —CN.

The phrase, “carbocyclic ring,” as used herein, refers to a hydrocarbonring system in which all the ring atoms are carbon. Exemplarycarbocyclic rings including cycloalkyls and phenyl.

The term “cycloalkyl,” as used herein, refers to a monocyclic saturatedor partially unsaturated hydrocarbon ring (carbocyclic) system, forexample, where each ring is either completely saturated or contains oneor more units of unsaturation, but where no ring is aromatic. Acycloalkyl can have 3-6 or 4-6 carbon atoms in its ring system, referredto herein as C₃-C₆ cycloalkyl or C₄-C₆ cycloalkyl, respectively.Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl,cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

The terms “halo” and “halogen,” as used herein, refer to fluoro (F),chloro (Cl), bromo (Br), and/or iodo (1).

The term “heteroatom,” as used herein, refers to an atom of any elementother than carbon or hydrogen and includes, for example, nitrogen (N),oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se).

The term “heterocyclic ring” or “heterocycloalkyl,” as used herein, isart-recognized and refer to saturated or partially unsaturated 3- to8-membered ring structures, whose ring system include one, two or threeheteroatoms, such as nitrogen, oxygen, and/or sulfur. A heterocyclicring can be fused to one or more phenyl, partially unsaturated, orsaturated rings.

Examples of heterocyclic ring include, but are not limited to,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, andpiperazinyl.

The terms “hydroxy” and “hydroxyl,” as used herein, refer to the radical—OH.

The term “oxo,” as used herein, refers to the radical ═O (double bondedoxygen).

The term “amino acid,” as used herein, includes any one of the followingalpha amino acids: isoleucine, alanine, leucine, asparagine, lysine,aspartate, methionine, cysteine, phenylalanine, glutamate, threonine,glutamine, tryptophan, glycine, valine, proline, arginine, serine,histidine, and tyrosine. An amino acid also can include otherart-recognized amino acids such as beta amino acids.

The term “compound,” as used herein, refers to the compound itself andits pharmaceutically acceptable salts, hydrates, esters and N-oxidesincluding its various stereoisomers and its isotopically-labelled forms,unless otherwise understood from the context of the description orexpressly limited to one particular form of the compound, i.e., thecompound itself, a specific stereoisomer and/or isotopically-labelledcompound, or a pharmaceutically acceptable salt, a hydrate, an ester, oran N-oxide thereof. It should be understood that a compound can refer toa pharmaceutically acceptable salt, or a hydrate, an ester or an N-oxideof a stereoisomer of the compound and/or an isotopically-labelledcompound.

The compounds of the disclosure can contain one or more chiral centersand/or double bonds and therefore, can exist as stereoisomers, such asgeometric isomers, and enantiomers or diastereomers. The term“stereoisomers,” when used herein, consists of all geometric isomers,enantiomers and/or diastereomers of the compound. For example, when acompound is shown with specific chiral center(s), the compound depictedwithout such chirality at that and other chiral centers of the compoundare within the scope of the present disclosure, i.e., the compounddepicted in two-dimensions with “flat” or “straight” bonds rather thanin three dimensions, for example, with solid or dashed wedge bonds.Stereospecific compounds may be designated by the symbols “R” or “S,”depending on the configuration of substituents around the stereogeniccarbon atom. The present disclosure encompasses all the variousstereoisomers of these compounds and mixtures thereof. Mixtures ofenantiomers or diastereomers can be designated “(±)” in nomenclature,but a skilled artisan will recognize that a structure can denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual enantiomers and diastereomers of compounds of the presentdisclosure can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns, or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures also can be resolved into their component enantiomersby well-known methods, such as chiral-phase gas chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations. See, for example, Carreira andKvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim,2009.

Geometric isomers, resulting from the arrangement of substituents arounda carbon-carbon double bond or arrangement of substituents around acycloalkyl or heterocycloalkyl, can also exist in the compounds of thepresent disclosure. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration, where the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

The disclosure also embraces isotopically-labeled compounds which areidentical to those compounds recited herein, except that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds describedherein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H (“D”), ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, acompound described herein can have one or more H atoms replaced withdeuterium.

Certain isotopically-labeled compounds (e.g., those labeled with ³H and¹⁴C) can be useful in compound and/or substrate tissue distributionassays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can beparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)can afford certain therapeutic advantages resulting from greatermetabolic stability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence can be preferred in some circumstances.Isotopically-labeled compounds can generally be prepared by followingprocedures analogous to those disclosed herein, for example, in theExamples section, by substituting an isotopically-labeled reagent for anon-isotopically-labeled reagent.

The phrases “pharmaceutically acceptable” and “pharmacologicallyacceptable,” as used herein, refer to compounds, molecular entities,compositions, materials, and/or dosage forms that do not produce anadverse, allergic or other untoward reaction when administered to ananimal, or a human, as appropriate. For human administration,preparations should meet sterility, pyrogenicity, general safety andpurity standards as required by FDA Office of Biologics standards.

The phrases “pharmaceutically acceptable carrier” and “pharmaceuticallyacceptable excipient,” as used herein, refer to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration.Pharmaceutical acceptable carriers can include phosphate buffered salinesolution, water, emulsions (e.g., such as an oil/water or water/oilemulsions), and various types of wetting agents. The compositions alsocan include stabilizers and preservatives.

The phrase “pharmaceutical composition,” as used herein, refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers. The pharmaceutical compositions can also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The terms “individual,” “patient,” and “subject,” as used herein, areused interchangeably and include any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and more preferably, humans. Thecompounds described in the disclosure can be administered to a mammal,such as a human, but can also be administered to other mammals such asan animal in need of veterinary treatment, for example, domestic animals(e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs,horses, and the like) and laboratory animals (e.g., rats, mice, guineapigs, and the like). The mammal treated in the methods described in thedisclosure is preferably a mammal in which treatment, for example, ofpain or depression, is desired.

The term “treating,” as used herein, includes any effect, for example,lessening, reducing, modulating, ameliorating, or eliminating, thatresults in the improvement of the condition, disease, disorder, and thelike, including one or more symptoms thereof. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “disorder” refers to and is used interchangeably with, theterms “disease,” “condition,” or “illness,” unless otherwise indicated.

The term “modulation,” as used herein, refers to and includes antagonism(e.g., inhibition), agonism, partial antagonism, and/or partial agonism.

The phrase “therapeutically effective amount,” as used herein, refers tothe amount of a compound (e.g., a disclosed compound) that will elicitthe biological or medical response of a tissue, system, animal or humanthat is being sought by the researcher, veterinarian, medical doctor orother clinician. The compounds described in the disclosure can beadministered in therapeutically effective amounts to treat a disease. Atherapeutically effective amount of a compound can be the quantityrequired to achieve a desired therapeutic and/or prophylactic effect,such as an amount which results in lessening of a symptom of a diseasesuch as depression.

As used herein, the term “pharmaceutically acceptable salt” refers toany salt of an acidic or a basic group that may be present in a compoundof the present disclosure, which salt is compatible with pharmaceuticaladministration. As is known to those of skill in the art, “salts” of thecompounds of the present disclosure may be derived from inorganic ororganic acids and bases.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentdisclosure compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (where W can be a C₁₋₄ alkyl group), and the like. For therapeuticuse, salts of the compounds of the present disclosure can bepharmaceutically acceptable. However, salts of acids and bases that arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.

Compounds included in the present compositions that are basic in natureare capable of forming a wide variety of salts with various inorganicand organic acids. The acids that can be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsare those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,sodium, lithium, zinc, potassium, and iron salts.

Compounds included in the present compositions that include a basic oracidic moiety can also form pharmaceutically acceptable salts withvarious amino acids. The compounds of the disclosure can contain bothacidic and basic groups; for example, one amino and one carboxylic acidgroup. In such a case, the compound can exist as an acid addition salt,a zwitterion, or a base salt.

The compounds disclosed herein can exist in a solvated form as well asan unsolvated form with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the disclosureembrace both solvated and unsolvated forms. In some embodiments, thecompound is amorphous. In certain embodiments, the compound is a singlepolymorph. In various embodiments, the compound is a mixture ofpolymorphs. In particular embodiments, the compound is in a crystallineform.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound described herein or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound described herein contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

If a compound described herein incorporates an amine functional group, aprodrug can be formed, for example, by creation of an amide orcarbamate, an N-acyloxyakyl derivative, an (oxodioxolenyl) methylderivative, an N-Mannich base, imine or enamine. In addition, asecondary amine can be metabolically cleaved to generate a bioactiveprimary amine, or a tertiary amine can metabolically cleaved to generatea bioactive primary or secondary amine. For examples, see Simplício, etal., Molecules 2008, 13, 519 and references therein.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure pertains.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present disclosure that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present disclosure that consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components.

Further, it should be understood that elements and/or features of acomposition or a method described herein can be combined in a variety ofways without departing from the spirit and scope of the presentdisclosure, whether explicit or implicit herein. For example, wherereference is made to a particular compound, that compound can be used invarious embodiments of compositions of the present disclosure and/or inmethods of the present disclosure, unless otherwise understood from thecontext. In other words, within this application, embodiments have beendescribed and depicted in a way that enables a clear and conciseapplication to be written and drawn, but it is intended and will beappreciated that embodiments can be variously combined or separatedwithout parting from the present teachings and disclosure(s). Forexample, it will be appreciated that all features described and depictedherein can be applicable to all aspects of the disclosure(s) describedand depicted herein.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle, unless the context is inappropriate. By way of example, “anelement” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

It should be understood that the expression “at least one of” includesindividually each of the recited objects after the expression and thevarious combinations of two or more of the recited objects unlessotherwise understood from the context and use. The expression “and/or”in connection with three or more recited objects should be understood tohave the same meaning unless otherwise understood from the context.

The use of the term “include,” “includes,” “including,” “have,” “has,”“having,” “contain,” “contains,” or “containing,” including grammaticalequivalents thereof, should be understood generally as open-ended andnon-limiting, for example, not excluding additional unrecited elementsor steps, unless otherwise specifically stated or understood from thecontext.

Where the use of the term “about” is before a quantitative value, thepresent disclosure also include the specific quantitative value itself,unless specifically stated otherwise. As used herein, the term “about”refers to a ±10% variation from the nominal value unless otherwiseindicated or inferred.

Where a percentage is provided with respect to an amount of a componentor material in a composition, the percentage should be understood to bea percentage based on weight, unless otherwise stated or understood fromthe context.

Where a molecular weight is provided and not an absolute value, forexample, of a polymer, then the molecular weight should be understood tobe an average molecule weight, unless otherwise stated or understoodfrom the context.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present disclosure remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

At various places in the present specification, substituents aredisclosed in groups or in ranges. It is specifically intended that thedescription include each and every individual subcombination of themembers of such groups and ranges. For example, the term “C₁₋₆ alkyl” isspecifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆,C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆,C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆ alkyl. By way of other examples,an integer in the range of 0 to 40 is specifically intended toindividually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Additionalexamples include that the phrase “optionally substituted with 1-5substituents” is specifically intended to individually disclose achemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2,0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.

The use of any and all examples, or exemplary language herein, forexample, “such as” or “including,” is intended merely to illustratebetter the present disclosure and does not pose a limitation on thescope of the disclosure unless claimed. No language in the specificationshould be construed as indicating any non-claimed element as essentialto the practice of the present disclosure.

Further, if a variable is not accompanied by a definition, then thevariable is defined as found elsewhere in the disclosure unlessunderstood to be different from the context. In addition, the definitionof each variable and/or substituent, for example, C₁-C₆ alkyl, R²,R^(b), w and the like, when it occurs more than once in any structure orcompound, can be independent of its definition elsewhere in the samestructure or compound.

Definitions of the variables and/or substituents in formulae and/orcompounds herein encompass multiple chemical groups. The presentdisclosure includes embodiments where, for example, i) the definition ofa variable and/or substituent is a single chemical group selected fromthose chemical groups set forth herein, ii) the definition is acollection of two or more of the chemical groups selected from those setforth herein, and iii) the compound is defined by a combination ofvariables and/or substituents in which the variables and/or substituentsare defined by (i) or (ii).

Various aspects of the disclosure are set forth herein under headingsand/or in sections for clarity; however, it is understood that allaspects, embodiments, or features of the disclosure described in oneparticular section are not to be limited to that particular section butrather can apply to any aspect, embodiment, or feature of the presentdisclosure.

Compounds

Disclosed compounds include a compound having the formula:

or a pharmaceutically acceptable salt and/or stereoisomer thereof,wherein:

-   -   X is NR¹ or CR²R²;    -   Y is NR¹ or CR²R², wherein one of X or Y is NR¹;    -   R¹ is selected from the group consisting of H, C₁-C₆alkyl,        phenyl, —C(O)—C₁-C₆alkyl, and —C(O)—O—C₁-C₆ alkyl;    -   q is 0 or 1;    -   r is 1 or 2;    -   R⁷ is independently selected from the group consisting of H,        —C₁-C₆alkyl, —S(O)_(w)—C₁C₃alkyl, cyano, and halogen;    -   R⁹ is independently selected from the group consisting of H,        —C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, cyano, and halogen, or R⁷ and        R⁹ taken together with the adjacent carbons to which they are        attached form a 3-membered carbocyclic ring which can be        optionally substituted by one or two substituents independently        selected from the group consisting of halogen, hydroxyl,        —C₁-C₃alkyl, —C₁-C₃alkoxy, —C(O)NR^(a)R^(b), and —NR^(a)R^(b);    -   R² is independently selected for each occurrence from the group        consisting of H, C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b)        and halogen;    -   R⁵ is independently selected for each occurrence from the group        consisting of H, C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b),        cyano and halogen;    -   R⁶ represents one or two optional substitutions each on one or        more available ring carbons, and is independently selected for        each occurrence from the group consisting of C₁-C₆alkyl,        —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen;    -   w is 0, 1, or 2;    -   R³ is selected from the group consisting of H, phenyl, C₁-C₆        alkyl, —C(O)R³¹ and —C(O)OR³²;    -   R³¹ and R³² are each independently H, C₁-C₆alkyl,        —C₃-C₆cycloalkyl, and phenyl; and    -   R^(a) and R^(b) are each independently for each occurrence        selected from the group consisting of H, phenyl, and C₁-C₃alkyl,        or R^(a) and R^(h) taken together with the nitrogen to which        they are attached form a 4-6 membered heterocyclic ring;        -   wherein any aforementioned C₁-C₆ alkyl, independently for            each occurrence, can be optionally substituted by one, two            or three substituents each independently selected from            —C(O)NR^(a)R^(b), —NR^(a)R^(b), hydroxyl,            S(O)_(w)—C₁-C₃alkyl (where w is 0, 1, or 2), SH, phenyl and            halogen, and any aforementioned phenyl, independently for            each occurrence, can be optionally substituted by one, two            or three substituents each independently selected from            —C(O)—C₁-C₃alkyl, hydroxyl, —C(O)— C₁-C₃alkyl, methyl, CF₃            and halogen.

In some embodiments, q can be 1. In certain embodiments, q can be 0. Insome embodiments, q can be 0 and r can be 2.

In some embodiments, X can be NR¹ and Y can be CR²R². In certainembodiments, R¹ can be C(O)—O—C₁-C₆ alkyl, —C(O)—C₁-C₆alkyl, C₁-C₆alkyl,or H.

In various embodiments, a disclosed compound has the formula:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof,where the variables R¹, R², R³, R⁵, R⁶, R⁷, and R⁹ are as definedherein.

In some embodiments, R¹ can be C(O)—C₁-C₆alkyl, where C(O)—C₁-C₆alkylcan be represented by:

wherein R^(a) and R^(b) can be each independently selected for eachoccurrence from the group consisting of hydrogen and —C₁-C₆alkyl.

In some embodiments, R¹ can be C₁-C₆alkyl. For example, R¹ can be

In some embodiments, R¹ can be C(O)—O—C₁-C₆ alkyl. For example, R¹ canbe tert-butyloxycarbonyl.

In some embodiments, R³ can be H. In certain embodiments, R³ can beselected from the group consisting of:

and R^(b) can be each independently selected for each occurrence fromthe group consisting of hydrogen and —C₁-C₆alkyl.

In certain embodiments, R¹ and/or R³ independently can be an amino acidor a derivative of an amino acid, for example, an alpha “amino amide”represented by H₂N—CH(amino acid side chain)-C(O)NH₂. In certainembodiments, the nitrogen atom of the amino group of the amino acid orthe amino acid derivative is a ring nitrogen in a chemical formuladescribed herein. In such embodiments, the carboxylic acid of the aminoacid or the amide group of an amino amide (amino acid derivative) is notwithin the ring structure, i.e., not a ring atom. In certainembodiments, the carboxylic acid group of the amino acid or the aminoacid derivative forms an amide bond with a ring nitrogen in a chemicalformula disclosed herein, thereby providing an amino amide, where theamino group of the amino amide is not within the ring structure, i.e.,not a ring atom. In certain embodiments, R¹ and/or R³ independently canbe an alpha amino acid, an alpha amino acid derivative, and/or anotheramino acid or amino acid derivative such as a beta amino acid or a betaamino acid derivative, for example, a beta amino amide.

In various embodiments, R² is H at each occurrence. In some embodiments,R⁵ is H at each occurrence. In certain embodiments, R⁶ is H. Inparticular embodiments, R⁷ is H at each occurrence. In some embodiments,R⁹ is H at each occurrence.

In some embodiments, a disclosed compound is selected from the compoundsdelineated in the Examples, and includes pharmaceutically acceptablesalts and/or stereoisomers thereof.

In certain embodiments, a disclosed compound includes one having theformula selected from the group consisting of:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, a disclosed compound includes one having theformula selected from the group consisting of:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

The compounds of the present disclosure and formulations thereof mayhave a plurality of chiral centers. Each chiral center may beindependently R, S, or any mixture of R and S. For example, in someembodiments, a chiral center may have an R:S ratio of between about100:0 and about 50:50 (“racemate”), between about 100:0 and about 75:25,between about 100:0 and about 85:15, between about 100:0 and about90:10, between about 100:0 and about 95:5, between about 100:0 and about98:2, between about 100:0 and about 99:1, between about 0:100 and 50:50,between about 0:100 and about 25:75, between about 0:100 and about15:85, between about 0:100 and about 10:90, between about 0:100 andabout 5:95, between about 0:100 and about 2:98, between about 0:100 andabout 1:99, between about 75:25 and 25:75, and about 50:50. Formulationsof the disclosed compounds comprising a greater ratio of one or moreisomers (i.e., R and/or S) may possess enhanced therapeuticcharacteristic relative to racemic formulations of a disclosed compoundsor mixture of compounds. In some instances, chemical formulas containthe descriptor “-(R)-” or “—(S)—” that is further attached to solidwedge or dashed wedge. This descriptor is intended to show a methinecarbon (CH) that is attached to three other substituents and has eitherthe indicated R or S configuration.

Disclosed compounds may provide for efficient cation channel opening atthe NMDA receptor, e.g. may bind or associate with the glutamate site orglycine site or other modulatory site of the NMDA receptor to assist inopening the cation channel. The disclosed compounds may be used toregulate (turn on or turn off) the NMDA receptor through action as anagonist or antagonist.

The compounds described herein, in some embodiments, may bind to aspecific NMDA receptor subtypes. For example, a disclosed compound maybind to one NMDA subtype and not another. In some embodiments, adisclosed compound may bind to one, or more than one NMDA subtype,and/or may have substantially less (or substantial no) binding activityto certain other NMDA subtypes.

The compounds as described herein may bind to NMDA receptors. Adisclosed compound may bind to the NMDA receptor resulting inagonist-like activity (facilitation) over a certain dosing range and/ormay bind to the NMDA receptor resulting in antagonist-like activity(inhibition) over a certain dosing range. In some embodiments, adisclosed compound may possess a potency that is 10-fold or greater thanthe activity of existing NMDA receptor modulators.

The disclosed compounds may exhibit a high therapeutic index. Thetherapeutic index, as used herein, refers to the ratio of the dose thatproduces a toxicity in 50% of the population (i.e., TD₅₀) to the minimumeffective dose for 50% of the population (i.e., ED₅₀). Thus, thetherapeutic index=(TD₅₀):(ED₅₀). In some embodiments, a disclosedcompound may have a therapeutic index of at least about 10:1, at leastabout 50:1, at least about 100:1, at least about 200:1, at least about500:1, or at least about 1000:1.

Compositions

In other aspects of the disclosure, a pharmaceutical formulation or apharmaceutical composition including a disclosed compound and apharmaceutically acceptable excipient is provided. In some embodiments,a pharmaceutical composition comprises a racemic mixture of one or moreof the disclosed compounds.

A formulation can be prepared in any of a variety of forms for use suchas for administering an active agent to a patient, who may be in needthereof, as are known in the pharmaceutical arts. For example, thepharmaceutical compositions of the present disclosure can be formulatedfor administration in solid or liquid form, including those adapted forthe following: (1) oral administration, for example, drenches (aqueousor non-aqueous solutions or suspensions), tablets (e.g., those targetedfor buccal, sublingual, and/or systemic absorption), boluses, powders,granules, and pastes for application to the tongue; (2) parenteraladministration by, for example, subcutaneous, intramuscular,intraperitoneal, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation; (3)topical administration, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; (4) intravaginalor intrarectal administration, for example, as a pessary, cream or foam;(5) sublingual administration; (6) ocular administration; (7)transdermal administration; or (8) nasal administration.

For example, pharmaceutical compositions of the disclosure can besuitable for delivery to the eye, i.e., ocularly. Related methods caninclude administering a pharmaceutically effective amount of a disclosedcompound or a pharmaceutical composition including a disclosed compoundto a patient in need thereof, for example, to an eye of the patient,where administering can be topically, subconjunctivally, subtenonly,intravitreally, retrobulbarly, peribulbarly, intracomerally, and/orsystemically.

Amounts of a disclosed compound as described herein in a formulation mayvary according to factors such as the disease state, age, sex, andweight of the individual. Dosage regimens may be adjusted to provide theoptimum therapeutic response. For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for themammalian subjects to be treated; each unit containing a predeterminedquantity of active compound calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier.

The specification for the dosage unit forms are dictated by and directlydependent on (a) the unique characteristics of the compound selected andthe particular therapeutic effect to be achieved, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage. The composition can be formulatedas a solution, microemulsion, liposome, or other ordered structuresuitable to high drug concentration. The carrier can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyethylene glycol, andthe like), and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol, sorbitol, or sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent which delays absorption, forexample, monostearate salts and gelatin.

The compounds can be administered in a time release formulation, forexample in a composition which includes a slow release polymer. Thecompounds can be prepared with carriers that will protect the compoundagainst rapid release, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers(PLG). Many methods for the preparation of such formulations aregenerally known to those skilled in the art.

Sterile injectable solutions can be prepared by incorporating thecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

In some embodiments, a compound can be formulated with one or moreadditional compounds that enhance the solubility of the compound.

Methods

Methods of the disclosure for treating a condition in a patient in needthereof include administering a therapeutically effective amount of acompound described herein or a composition including such a compound. Insome embodiments, the condition may be a mental condition. For example,a mental illness may be treated. In another aspect, a nervous systemcondition may be treated. For example, a condition that affects thecentral nervous system, the peripheral nervous system, and/or the eyemay be treated. In some embodiments, neurodegenerative diseases may betreated.

In some embodiments, the methods include administering a compound totreat patients suffering from autism, anxiety, depression, bipolardisorder, attention deficit disorder, attention deficit hyperactivitydisorder (ADHD), schizophrenia, a psychotic disorder, a psychoticsymptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia,post-traumatic stress syndrome, a behavior disorder, an impulse controldisorder, a substance abuse disorder (e.g., a withdrawal symptom, opiateaddiction, nicotine addiction, and ethanol addition), a sleep disorder,a memory disorder (e.g., a deficit, loss, or reduced ability to make newmemories), a learning disorder, urinary incontinence, multiple systematrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down'ssyndrome, fragile X syndrome, tuberous sclerosis,olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced opticneuritis, ischemic retinopathy, diabetic retinopathy, glaucoma,dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea,spasticity, myoclonus, muscle spasm, infantile spasm, Tourette'ssyndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumaticbrain injury, cardiac arrest, myelopathy, spinal cord injury, peripheralneuropathy, acute neuropathic pain, and chronic neuropathic pain.

In some embodiments, methods of treating a memory disorder associatedwith aging, schizophrenia, special learning disorders, seizures,post-stroke convulsions, brain ischemia, hypoglycemia, cardiac arrest,epilepsy, Lewy body dementia, migraine, AIDS dementia, Huntington'schorea, Parkinson's disease, early stage Alzheimer's disease, andAlzheimer's disease are provided.

In certain embodiments, methods for treating schizophrenia are provided.For example, paranoid type schizophrenia, disorganized typeschizophrenia (i.e., hebephrenic schizophrenia), catatonic typeschizophrenia, undifferentiated type schizophrenia, residual typeschizophrenia, post-schizophrenic depression, and simple schizophreniamay be treated using the methods and compositions disclosed herein.Psychotic disorders such as schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders, andpsychotic disorders with delusions or hallucinations may also be treatedusing the compositions disclosed herein.

Paranoid schizophrenia may be characterized where delusions or auditoryhallucinations are present, but thought disorder, disorganized behavior,or affective flattening are not. Delusions may be persecutory and/orgrandiose, but in addition to these, other themes such as jealousy,religiosity, or somatization may also be present. Disorganized typeschizophrenia may be characterized where thought disorder and flataffect are present together. Catatonic type schizophrenia may becharacterized where the patient may be almost immobile or exhibitagitated, purposeless movement. Symptoms can include catatonic stuporand waxy flexibility. Undifferentiated type schizophrenia may becharacterized where psychotic symptoms are present but the criteria forparanoid, disorganized, or catatonic types have not been met. Residualtype schizophrenia may be characterized where positive symptoms arepresent at a low intensity only. Post-schizophrenic depression may becharacterized where a depressive episode arises in the aftermath of aschizophrenic illness where some low-level schizophrenic symptoms maystill be present. Simple schizophrenia may be characterized by insidiousand progressive development of prominent negative symptoms with nohistory of psychotic episodes.

In some embodiments, methods are provided for treating psychoticsymptoms that may be present in other mental disorders, including, butnot limited to, bipolar disorder, borderline personality disorder, drugintoxication, and drug-induced psychosis. In some embodiments, methodsfor treating delusions (e.g., “non-bizarre”) that may be present in, forexample, delusional disorder are provided.

In various embodiments, methods for treating social withdrawal inconditions including, but not limited to, social anxiety disorder,avoidant personality disorder, and schizotypal personality disorder areprovided.

In some embodiments, the disclosure provides methods for treating aneurodevelopmental disorder related to synaptic dysfunction in a patientin need thereof, where the methods generally include administering tothe patient a therapeutically effective amount of a disclosed compound,or a pharmaceutical composition including a disclosed compound. Incertain embodiments, the neurodevelopmental disorder related to synapticdysfunction can be Rett syndrome also known as cerebroatrophichyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder),CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberoussclerosis (e.g., a TSC1 disorder and/or a TSC2 disorder),neurofibromatosis (e.g., a NF1 disorder), Angelman syndrome (e.g., aUBE3A disorder), the PTEN hamartoma tumor syndrome, Phelan-McDermidsyndrome (e.g., a SHANK3 disorder), or infantile spasms. In particularembodiments, the neurodevelopmental disorder can be caused by mutationsin the neuroligin (e.g., a NLGN3 disorder and/or a NLGN2 disorder)and/or the neurexin (e.g., a NRXN1 disorder).

In some embodiments, methods are provided for treating neuropathic pain.The neuropathic pain may be acute or chronic. In some cases, theneuropathic pain may be associated with a condition such as herpes, HIV,traumatic nerve injury, stroke, post-ischenia, chronic back pain,post-herpetic neuralgia, fibromyalgia, reflex sympathetic dystrophy,complex regional pain syndrome, spinal cord injury, sciatica, phantomlimb pain, diabetic neuropathy such as diabetic peripheral neuropathy(“DPN”), and cancer chemotherapeutic-induced neuropathic pain. Methodsfor enhancing pain relief and for providing analgesia to a patient arealso provided.

Further methods include a method of treating autism and/or an autismspectrum disorder in a patient need thereof, comprising administering aneffective amount of a compound to the patient. In certain embodiments, amethod for reducing the symptoms of autism in a patient in need thereofcomprises administering an effective amount of a disclosed compound tothe patient. For example, upon administration, the compound may decreasethe incidence of one or more symptoms of autism such as eye contactavoidance, failure to socialize, attention deficit, poor mood,hyperactivity, abnormal sound sensitivity, inappropriate speech,disrupted sleep, and perseveration. Such decreased incidence may bemeasured relative to the incidence in the untreated individual or anuntreated individual(s).

Also provided herein is a method of modulating an autism target geneexpression in a cell comprising contacting a cell with an effectiveamount of a compound described herein. The autism gene expression may befor example, selected from ABAT, APOE, CHRNA4, GABRA5, GFAP, GRIN2A,PDYN, and PENK. In some embodiments, a method of modulating synapticplasticity in a patient suffering from a synaptic plasticity relateddisorder is provided, comprising administering to the patient aneffective amount of a compound.

In some embodiments, a method of treating Alzheimer's disease, or e.g.,treatment of memory loss that e.g., accompanies early stage Alzheimer'sdisease, in a patient in need thereof is provided, comprisingadministering a compound. Also provided herein is a method of modulatingan Alzheimer's amyloid protein (e.g., beta amyloid peptide, e.g. theisoform Aβ₁₋₄₂), in-vitro or in-vivo (e.g. in a cell) comprisingcontacting the protein with an effective amount of a compound isdisclosed. For example, in some embodiments, a compound may block theability of such amyloid protein to inhibit long-term potentiation inhippocampal slices as well as apoptotic neuronal cell death. In someembodiments, a disclosed compound may provide neuroprotective propertiesto a Alzheimer's patient in need thereof, for example, may provide atherapeutic effect on later stage Alzheimer's-associated neuronal celldeath.

In certain embodiments, the disclosed methods include treating apsychosis or a pseudobulbar affect (“PBA”) that is induced by anothercondition such as a stroke, amyotrophic lateral sclerosis (ALS or LouGehrig's disease), multiple sclerosis, traumatic brain injury,Alzheimer's disease, dementia, and/or Parkinson's disease. Such methods,as with other methods of the disclosure, include administration of apharmaceutically effective amount of a disclosed compound to a patientin need thereof.

In some embodiments, a method of treating depression includesadministering a therapeutically effective amount of a compound describedherein. In some embodiments, the treatment may relieve depression or asymptom of depression without affecting behavior or motor coordinationand without inducing or promoting seizure activity. Exemplary depressionconditions that are expected to be treated according to this aspectinclude, but are not limited to, major depressive disorder, dysthymicdisorder, psychotic depression, postpartum depression, premenstrualsyndrome, premenstrual dysphoric disorder, seasonal affective disorder(SAD), bipolar disorder (or manic depressive disorder), mood disorder,and depressions caused by chronic medical conditions such as cancer orchronic pain, chemotherapy, chronic stress, and post traumatic stressdisorders. In addition, patients suffering from any form of depressionoften experience anxiety. Various symptoms associated with anxietyinclude fear, panic, heart palpitations, shortness of breath, fatigue,nausea, and headaches among others. Anxiety or any of the symptomsthereof may be treated by administering a compound as described herein.

Also provided herein are methods of treating a condition intreatment-resistant patients, e.g., patients suffering from a mental orcentral nervous system condition that does not, and/or has not,responded to adequate courses of at least one, or at least two, othercompounds or therapeutics. For example, provided herein is a method oftreating depression in a treatment resistant patient, comprising a)optionally identifying the patient as treatment resistant and b)administering an effective dose of a compound to said patient.

In some embodiments, a compound described herein may be used for acutecare of a patient. For example, a compound may be administered to apatient to treat a particular episode (e.g., a severe episode) of acondition disclosed herein.

Also provided herein are combination therapies comprising a compound ofthe disclosure in combination with one or more other active agents. Forexample, a compound may be combined with one or more antidepressants,such as tricyclic antidepressants, MAO-I's, SSRI's, and double andtriple uptake inhibitors and/or anxiolytic drugs. Exemplary drugs thatmay be used in combination with a compound include Anafranil, Adapin,Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil,Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox,Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel(trazodone), and Ludiomill. In another example, a compound may becombined with an antipsychotic medication. Non-limiting examples ofantipsychotics include butyrophenones, phenothiazines, thioxanthenes,clozapine, olanzapine, risperidone, quetiapine, ziprasidone,amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole,lurasidone, and aripiprazole. It should be understood that combinationsof a compound and one or more of the above therapeutics may be used fortreatment of any suitable condition and are not limited to use asantidepressants or antipsychotics.

EXAMPLES

The following examples are provided for illustrative purposes only, andare not intended to limit the scope of the disclosure.

The following abbreviations may be used herein and have the indicateddefinitions: Ac is acetyl (—C(O)CH₃), AIDS is acquired immune deficiencysyndrome, Boc and BOC are tert-butoxycarbonyl, Boc₂O is di-tert-butyldicarbonate, Bn is benzyl, DCM is dichloromethane, DIPEA isN,N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMSO isdimethyl sulfoxide, ESI is electrospray ionization, EtOAc is ethylacetate, h is hour, HIV is human immunodeficiency virus, HPLC is highperformance liquid chromatography, LCMS is liquid chromatography/massspectrometry, LiHMDS is lithium hexamethyldisilazane, NMDAR isN-methyl-d-apartate receptor, NMR is nuclear magnetic resonance, RT isroom temperature (e.g., from about 20° C. to about 25° C.), TLC is thinlayer chromatography, TFA is trifluoroacetic acid, and THF istetrahydrofuran.

Example 1: Synthesis of Exemplary Compounds

Synthesis of ethyl piperidine-3-carboxylate hydrochloride (1)

To a stirring solution of piperidine-3-carboxylic acid (SM) (20 g, 154.8mmol) in EtOH was added thionyl chloride (45 ml, 619.2 mmol) at 0° C.and heated to reflux for 24 h. The reaction mixture was warmed to RT andconcentrated under reduced pressure. Crude material was triturated withdiethyl ether and dried to afford compound 1. HCl salt (29 g, 99%) asthick syrup.

¹H-NMR: (400 MHz, DMSO-d₆): δ 9.40 (s, 1H), 9.25 (s, 1H), 4.09 (q, J=7.2Hz, 2H), 3.32. 3.13 (m, 2H), 2.94-2.75 (m, 3H), 1.99-1.96 (m, 1H),1.77-1.71 (m, 2H), 1.60-1.58 (1H), 1.16 (t, J=7.2 Hz, 3H).

LCMS (ESI): m/z 157.3 [M⁺]

Synthesis of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate (2)

To a solution of compound 1. HCl salt (30 g, 154.9 mmol) in CH₂Cl₂ (600mL) was added Et₃N (65 mL, 464.7 mmol) at 0° C. and stirred for 10 min.Then Boc-anhydride (40 mL, 185.8 mmol) at 0° C. warmed to RT and stirredfor 16 h. After consumption of the starting material (by TLC), thereaction was diluted with DCM (200 mL) and washed with water (3×200 mL).Organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford crude compound which was purified by columnchromatography by eluting with 20% EtOAc/hexanes to obtain compound 2(34 g, 85%) as thick syrup.

¹H-NMR: (400 MHz, DMSO-d₆): δ 4.06 (q, J=7.2 Hz, 2H), 3.89. 3.85 (m,1H), 3.64. 3.59 (m, 1H), 2.93-2.88 (m, 2H), 2.42. 2.37 (m, 1H),1.89-1.86 (m, 1H), 1.63-1.54 (m, 2H), 1.38 (s, 9H), 1.37-1.34 (m, 1H),1.18 (t, J=7.2 Hz, 3H).

LCMS (ESI): m/z 156.1 [(M⁺+1)-Boc]

Synthesis of 1-(tert-butyl) 3-ethyl3-(cyanomethyl)piperidine-1,3-dicarboxylate (3)

To a stirring solution of compound 2 (15 g, 58.3 mmol) in THF (120 mL)was added LiHMDS (1M in THF) (116 mL, 116.7 mmol) drop wise at −40° C.and stirred for 15 minutes. Then bromo acetonitrile (8.4 g, 70.1 mmol)was added drop wise at −40° C. and stirred for 5 h. After consumption ofthe starting material (by TLC), the reaction was quenched with aqueousNH₄Cl solution (100 mL) and extracted with EtOAc (2×200 mL). Thecombined organic layer was washed with water (2×150 mL) followed bybrine solution (2×100 mL). The organic layer was dried over Na₂SO₄ andconcentrated to obtain crude compound which was purified by columnchromatography by eluting 30% EtOAc/hexanes to afford compound 3 (3 g,17%) as thick syrup.

¹H NMR (400 MHz, DMSO-d₆): δ 4.16 (q, J=7.2 Hz, 2H), 3.78-3.72 (m, 1H),3.56-3.52 (m, 1H), 3.23-3.12 (m, 2H), 2.77-2.68 (m, 2H), 2.01-1.94 (m,1H), 1.68-1.58 (m, 3H), 1.39 (s, 9H), 1.24 (t, J=7.1 Hz, 3H).

LCMS (ESI): m/z 197.3 [(M⁺+1)-Boc]

Synthesis of tert-butyl 1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(4)

To a stirring solution of compound 3 (2 g, 6.75 mmol) in ethanol (20 mL)was added Raney nickel (2 g) at RT under nitrogen atmosphere and thenallowed to stir for 16 h under H, atmosphere. Then methanolic ammonia (4mL) was added to the reaction mixture and continued stirring for 16 hunder H₂ atmosphere (balloon pressure). After completion of the reactionby TLC, the reaction mixture was filtered through a pad of celite andthe filtrate was concentrated under reduced pressure. Crude material waspurified by combiflash column chromatography by eluting with 50%EtOAc/hexanes to afford to afford racemic compound 4 (750 mg) followedby chiral HPLC purification to obtain RE-1 (300 mg, %) and RA-1 (310 mg,%) as off white solids.

RE-1

¹H NMR (400 MHz, DMSO-d₆): δ 7.64 (s, 1H), 3.97-3.82 (m, 1H), 3.66 (brd, J=1.5 Hz, 1H), 3.15 (br t, J=7.0 Hz, 2H), 2.86-2.61 (m, 2H),1.97-1.86 (m, 1H), 1.84-1.74 (m, 1H), 1.70-1.53 (m, 2H), 1.46 (br d,J=14.4 Hz, 1H), 1.39 (s, 10H).

LCMS (ESI): m/z 255.3 [M⁺+1]

HPLC: 99.45%

ChiralHPLC: 100.00%

RA-1

¹H NMR (400 MHz, DMSO-d₆): δ 7.64 (s, 1H), 3.89 (br d, J=7.7 Hz, 1H),3.66 (br s, 1H), 3.15 (br t, J=7.0 Hz, 2H), 2.84-2.63 (m, 2H), 1.96-1.87(m, 1H), 1.84-1.74 (m, 1H), 1.70-1.54 (m, 2H), 1.49-1.44 (m, 2H), 1.39(s, 9H).

LCMS (ESI): m/z 255.3 └M⁺+1┘

HPLC: 99.55%

ChiralHPLC: 100.00%

Synthesis of 2,7-diazaspiro[4.5]decan-1-one (RB-1·HCl)

To a stirring solution of RE-1 (201 mg, 0.79 mmol) in CH₂Cl₂ (5 mL) wasadded 2 M HCl-1, 4-Dioxane (4 mL) at 0° C. warmed to RT and stirred for2 h, the reaction mixture was concentrated under reduced pressure toafford crude compound which was triturated with ether and n-pentane(2×20 mL) and dried to obtain RB-1·HCl (148 g, 99%) as off white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (br s, 2H), 7.92 (s, 1H), 3.25-3.15(m, 2H), 3.08-2.91 (m, 4H), 2.13-2.09 (m, 1H), 1.98-1.88 (m, 1H),1.86-1.76 (m, 1H), 1.74-1.63 (m, 2H), 1.59-1.50 (m, 1H).

LCMS (ESI): m/z 155.0 [M⁺+1]

HPLC: 99.55%

Chiral HPLC: 100.00%

Synthesis of 2,7-diazaspiro[4.5]decan-1-one (RC-1·HCl)

To a stirring solution of RA-1 (218 mg, 0.85 mmol) in CH₂Cl₂ (5 mL) wasadded 2 M HCl-1,4-Dioxane (4 mL) at 0° C., warmed to RT and stirred for2 h. the reaction mixture was concentrated under reduced pressure toafford crude compound which was triturated with ether and n-pentane(2×20 mL) and dried to obtain RC-1·HCl (150 g, 92%) as off white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.85 (br s, 2H), 7.91 (s, 1H), 3.24-3.16(m, 2H), 3.10-2.88 (m, 4H), 2.16-2.12 (m, 1H), 1.98-1.90 (m, 1H),1.86-1.75 (m, 1H), 1.75-1.63 (m, 2H), 1.57-1.52 (m, 1H).

LCMS (ESI): m/z 155.0 [M⁺+1]

HPLC: 99.65%

ChiralHPLC: 100.00%

Example 2

Following the above procedures, the following compounds were or areprepared. It should be appreciated that the compound in the first columnis a different stereoisomer, for example, a different enantiomer and/ordifferent diastereomer, from the compound in the second column.

Structure Compound

RE-1

RA-1

RB-1

RC-1

RG-601

RG-602

RG-603

RG-604

RG-605

RG-606

RG-607

RG-608

RG-609

RG-610

RG-611

RG-612

RG-613

RG-614

RG-615

RG-616

RG-617

RG-618

RG-619

RG-620

RG-621

RG-622

RG-623

RG-624

RG-625

RG-626

RG-627

RG-628

RG-629

RG-630

RG-631

RG-632

RG-633

RG-634

RG-635

RG-636

RG-637

RG-638

RG-639

RG-640

RG-641

RG-642

RG-643

RG-644

RG-645

RG-646

RG-647

RG-648

RG-649

RG-650

RG-651

RG-652

RG-653

RG-654

RG-655

RG-656

RG-657

RG-658

RG-659

RG-660

RG-661

RG-662

RG-663

RG-664

RG-665

RG-666

RG-667

RG-668

RG-669

RG-670

RG-671

RG-672

RG-673

RG-674

RG-675

RG-676

RG-677

RG-678

RG-679

RG-680

Example 3: Synthesis of Exemplary Compounds

Synthesis of methyl L-prolinate (1)

To a stirred solution of L-proline SM 1 (100.0 g, 869 mmol) in MeOH (1L), thionyl chloride (100 mL) was added at 0° C. heated to 75° C. andstirred for 16 h. After consumption of the starting material (by TLC),the reaction mixture was concentrated under reduced pressure to affordcompound 1 (140 g, crude) as thick oil (HCl salt). Crude compound wasuse as such for next step without purification.

¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (hr s, 1H), 9.13 (hr s, 1H), 4.35 (m,1H), 3.75 (s, 3H), 3.26-3.11 (m, 2H), 2.28-2.20 (m, 1H), 2.05-1.83 (in,3H).

Synthesis of 1-(tert-butyl) 2-methyl (S)-pyrrolidine-1,2-dicarboxylate(2)

To a stirred solution of compound 1 (140.0 g, 0.848 mol) in CH₂Cl₂ (1.4L), triethylamine (295 mL, 2.12 mmol) was added at 0° C. and stirred for15 min. Boc anhydride (240 g, 1.10 mmol) was added drop wise at 0° C.over a period of 30 min followed by addition of DMAP (20.7 g, 0.169mmol). The reaction mixture was warmed to RT and stirred for 3 h. Afterconsumption of the starting material (by TLC), the reaction mixture wasquenched with ice-cold water (500 mL) and extracted with CH₂Cl₂ (3×300mL). Combined organic layer was washed with brine (150 mL), dried overNa₂SO₄ and concentrated under reduced pressure to afford crude compound.The crude compound was purified by column chromatography with 20-30%EtOAc/hexanes to obtain compound 2 (190.0 g, 98%) as thick oil.

¹H NMR (400 MHz, DMSO-d₆) δ 4.18-413 (m, 1H), 3.63 (m, 3H), 3.41-3.24(m, 2H), 2.28-2.11 (m, 1H), 1.90-1.73 (m, 3H), 1.32 (m, 9H).

Synthesis of 1-(tert-butyl) 2-methyl2-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (3)

To a stirred solution of compound 2 (20.0 g, 93.4 mmol) in THF (150 mL),LiHMDS (140 mL, 140 mmol) was added at −78° C. and stirred for 30 min.Bromoacetonitrile (12.3 mL, 102 mmol) was added at −78° C.; warmed to RTand stirred for 4 h. After consumption of the starting material (byTLC), the reaction mixture was quenched with saturated NH₄Cl solution(300 mL) and extracted with EtOAc (3×300 mL). Combined organic layer waswashed with brine (100 mL), dried over Na₂SO₄ and concentrated underreduced pressure to give crude product. Obtained crude compound waspurified by column chromatography using 40% EtOAc/hexane to provideenantiomeric mixture of compound 3 (15 g, 63%) as thick oil.

¹H NMR (400 MHz, DMSO-d₆) δ 3.64 (m, 3H), 3.57-3.46 (m, 1H), 3.42-3.36(m, 1H), 3.26-3.09 (m, 5H), 2.25-2.16 (m, 2H), 2.04-1.83 (m, 2H), 1.37(m, 9H).

Synthesis of 1-(tert-butyl) 2-methyl2-(2-aminoethyl)pyrrolidine-1,2-dicarboxylate (4)

To a stirred solution of compound 3 (5.0 g, 18.6 mmol) in THF: MeOH(1:1, 200 mL), Raney nickel (4.0 g) was added at room temperature andstirred for 48 h at 50° C. under H₂ atmosphere. After consumption of thestarting material (by TLC), the reaction mixture was filtered through apad of celite and the pad was washed with MeOH (50 mL). The crudecompound was purified by column chromatography using 5% MeOH/CH₂Cl₂ toprovide enantiomeric mixture of compound 4 (2.5 g, 50%) as thick oil.

Synthesis of tert-butyl 6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(RM-1 & RT-1)

To a stirred solution of compound 4 (10.0 g, 36.9 mmol) in toluene (100mL), DIPEA (7.7 mL, 44.2 mmol) was added and reaction mixture was heatedto reflux for 36 h. After consumption of the starting material (by TLC),reaction mixture was evaporated under reduced pressure. Crude materialwas purified by Prep HPLC to obtain two separated isomers of compoundRM-1 & RT-1 as thick oil.

Analytical data for RM-1:

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (m, 1H), 3.40-3.30 (m, 1H), 3.25-3.09(m, 3H), 2.35-2.30 (m, 1H), 1.98-1.72 (m, 5H), 1.42 (s, 9H).

LCMS (ESI): m/z 263 [M⁺+Na]

HPLC: 95.4%

Chiral HPLC: 100%

Analytical data for RT-1

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 3.40-3.30 (m, 1H), 3.25-3.09(m, 3H), 2.35-2.30 (m, 1H), 1.98-1.70 (m, 5H), 1.45 (s, 9H).

LCMS (ESI): m/z 263 [M⁺+Na]

HPLC: 97.1%

Chiral HPLC: 100% Synthesis of 1,7-diazaspiro[4.4]nonan-6-one (RW-1 &RX-1):

To a stirred solution of compound 5 (1.5 g, 6.07 mmol) in CH₂Cl₂ (7 mL),trifluoroacetic (7 mL) was added and stirred at room temperature for 3h. After consumption of the starting material (by TLC), the reactionmixture was concentrated under reduced pressure to obtain compound as aTFA salt. Obtained salt was dissolved in THF (5 ml), triethylamine (5mL) was added and then stirred at room temperature for 5 h. The crudecompound was purified by Prep HPLC to afford two separated isomers ofcompound RW-1 & RX-1 (free base) as thick oil.

Analytical data for RW-1

¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (s, 1H), 3.20-3.03 (m, 2H), 3.01-2.97(m, 1H), 2.78-2.65 (m, 1H), 2.20-2.14 (brs, 1H), 1.99-1.80 (m, 2H),1.78-1.60 (m, 4H).

LCMS (ESI): m/z 141.2 └M⁺+1┘

HPLC: 97.9%

Chiral HPLC: 100%

Analytical data for RX-1:

¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (s, 1H), 3.19-3.02 (m, 2H), 3.01-2.97(m, 1H), 2.78-2.70 (m, 1H), 1.98-1.80 (m, 2H), 1.78-1.60 (m, 4H).

LCMS (ESI): m/z 141.3 └M⁺+1┘

HPLC: 99.4%

Chiral HPLC: 99.0%

Example 4

Following the above procedures, the following compounds were or areprepared. It should be appreciated that the compound in the first columnis a different stereoisomer, for example, a different enantiomer and/ordifferent diastereomer, from the compound in the second column.

Structure Compound

RM-1

RT-1

RW-1

RX-1

RZ-401

RZ-402

RZ-403

RZ-404

RZ-405

RZ-406

RZ-407

RZ-408

RZ-409

RZ-410

RZ-411

RZ-412

RZ-413

RZ-414

RZ-415

RZ-416

RZ-417

RZ-418

RZ-419

RZ-420

RZ-421

RZ-422

RZ-423

RZ-424

RZ-425

RZ-426

RZ-427

RZ-428

RZ-429

RZ-430

RZ-431

RZ-432

RZ-433

RZ-434

RZ-435

RZ-436

RZ-437

RZ-438

RZ-439

RZ-440

RZ-441

RZ-442

RZ-443

RZ-444

RZ-445

RZ-446

RZ-447

RZ-448

RZ-449

RZ-450

RZ-451

RZ-452

RZ-453

RZ-454

RZ-455

RZ-456

RZ-457

RZ-458

RZ-459

RZ-460

RZ-461

RZ-462

RZ-463

RZ-464

RZ-465

RZ-466

RZ-467

RZ-468

RZ-469

RZ-470

RZ-471

RZ-472

RZ-473

RZ-474

RZ-475

RZ-476

RZ-477

RZ-478

RZ-479

RZ-480

RZ-481

RZ-482

RZ-483

RZ-484

RZ-485

RZ-486

RZ-487

RZ-488

RZ-489

RZ-490

RZ-491

RZ-492

RZ-493

RZ-494

RZ-495

RZ-496

RZ-497

RZ-498

RZ-499

RZ-500

RZ-501

RZ-502

RZ-503

RZ-504

RZ-505

RZ-506

RZ-507

RZ-508

RZ-509

RZ-510

RZ-511

RZ-512

RZ-513

RZ-514

RZ-515

RZ-516

RZ-517

RZ-518

Example 5

This example demonstrates the positive emotional learning (PEL) test.Experiments were conducted as described in Burgdorf et al., “The effectof selective breeding for differential rates of 50-kHz ultrasonicvocalizations on emotional behavior in rats,” Devel. Psychobiol.,51:34-46 (2009). Rat 50-kH-z ultrasonic vocalization (hedonic USVs) is avalidated model for the study of positive affective state and is bestelicited by rough-and-tumble play. 50-kHz ultrasonic vocalizations havepreviously been shown to be positively correlated with reward andappetitive social behavior in rats, and to reflect a positive affectivestate.

The PEL assay measures the acquisition of positive (hedonic) 50-kHzultrasonic vocalizations (USVs) to a social stimulus, heterospecificrough and tumble play stimulation. Heterospecific rough-and-tumble playstimulation was administered by the experimenter's right hand. One hourafter administration of test compound or vehicle negative control (0.5%sodium carboxymethyl cellulose in 0.9% sterile saline vehicle), animalsreceived 3 min of heterospecific rough-and-tumble play that consisted ofalternating 15 sec blocks of heterospecific play and 15 sec ofno-stimulation. High frequency ultrasonic vocalizations (USVs) wererecorded and analyzed by sonogram with Avasoft SASlab Pro (Germany) aspreviously described by Burgdorf et al., “Positive emotional learning isregulated in the medial prefrontal cortex by GluN2B-containing NMDAreceptors,” Neuroscience, 192:515-523 (2011). Frequency modulated 50-kHzUSVs that occurred during each of the no-stimulation periods werequantified to measure PEL. Animals were not habituated to playstimulation before testing. Positive emotional learning was measuredduring the conditioned stimulus (CS) trials preceding the tickleunconditioned stimulus (UCS) trials. Animals received 15 second trialsconsisting of 6 CS and 6 UCS trials each (3 min total).

The table below summarizes the findings. As each experiment includes itsown vehicle group, an example (typical) vehicle score is shown. Maxeffect (mean number of 50 kHz USVs per 15 seconds) is reported as{circumflex over ( )}: <6.0; *: 6.0-7.6; **: 7.7-10; ***:10.1-20

Dose Compound Route (mg/kg) Max Effect Vehicle PO NA {circumflex over( )} RE-1 PO .001-1 *** RA-1 PO 0.1 *** RB-1 PO .001-1 *** RC-1 PO.001-1 *** RW-1 PO 0.1 ** RM-1 PO .001-1 *** RT-1 PO 0.1 **

Example 6

Assays were conducted as described by Moskal et al., “GLYX-13: amonoclonal antibody-derived peptide that acts as an N-methyl-D-aspartatereceptor modulator,” Neuropharmacology, 49, 1077-87, 2005. These studieswere designed to determine if the test compounds act to facilitate NMDARactivation in NMDAR2A, NMDAR2B, NMDAR2C or NMDAR2D expressing HEK cellmembranes as measured by increases in [³H]MK-801 binding.

In the assay, 300 μg of NMDAR expressing HEK cell membrane extractprotein was preincubated for 15 minutes at 25° C. in the presence ofsaturating concentrations of glutamate (50 μM) and varyingconcentrations of test compound (1×10⁻¹⁵M-1×10⁻⁷M), or 1 mM glycine.Following the addition of 0.3 μCi of [³H]MK-801 (22.5 Ci/mmol),reactions were again incubated for 15 minutes at 25° C. (nonequilibriumconditions). Bound and free [³H]MK-801 were separated via rapidfiltration using a Brandel apparatus.

In analyzing the data, the DPM (disintegrations per minute) of[³H]MK-801 remaining on the filter were measured for each concentrationof test compound or for 1 mM glycine. The DPM values for eachconcentration of a ligand (N=2) were averaged. The baseline value wasdetermined from the best fit curve of the DPM values modeled using theGraphPad program and the log(agonist) vs. response (three parameters)algorithm was then subtracted from all points in the dataset. The %maximal [³H]MK-801 binding was then calculated relative to that of 1 mMglycine: all baseline subtracted DPM values were divided by the averagevalue for 1 mM glycine. The EC₅₀ and % maximal activity were thenobtained from the best fit curve of the % maximal └³H┘ MK-801 bindingdata modelled using the GraphPad program and the log(agonist) vs.response (three parameters) algorithm.

The tables below summarize the results for the wild type NMDAR agonistsNMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D, and whether the compound is notan agonist (−), is an agonist (+), or is a strong agonist (++), wherecolumn A is based on the % maximal [³H]MK-801 binding relative to 1 mMglycine (−=0; <100%=+; and >100%=++); and column B is based on log EC₅₀values (0=−; >1×10⁻⁹ M (e.g., −8)=+; and <1×10⁻⁹ M (e.g., −10)=++).

NMDAR2A NMDAR2B Compound A B A B RE-1 − − + ++ RA-1 + + + ++ RB-1 + ++++ − RC-1 + ++ ++ ++ RW-1 + + + ++ RX-1 − − − − RM-1 + ++ ++ ++ RT-1 +++ + ++ RG-619 − − − − RG-603 + + + ++ RG-601 + ++ + ++ RG-602 + ++ + ++RG-605 + ++ − − RG-606 − − + ++ RG-623 − − + ++ RG-621 + ++ ++ ++ RG-609− − − − RG-610 − − − − RZ-405 + ++ ++ + RZ-406 − − + ++ RZ-403 − − ++ ++RZ-404 + ++ − − RE-1 − − + ++ RA-1 + ++ − − RB-1 + ++ + + RC-1 + ++ + ++RM-1 + ++ + ++ RG-601 + ++ ++ ++ RG-602 ++ + + ++ RG-605 − − − − RG-606− − − − RC-1 − − − − RZ-405 + ++ + ++

Example 7

Sprague Dawley rats were dosed intravenously using a normal salineformulation containing 2 mg/kg of the compounds identified in the belowtable (except for the first four compounds that were delivered in 5%NMP, 5% Solutol® HS and 90% normal saline formulation). The table belowsummarizes the results of the IV pharmacokinetics.

AUC_(last) Cl C₀ (hr*ng/ T_(1/2) (mL/min/ V_(ss) Compound (ng/mL) mL)(hr) kg) (L/kg) RE-1 589.9 135.9 0.27 NR 4.12 RA-1 1247.08 234.08 0.19NR 1.69 RB-1 2065.2 1261 3.35 25.81 2.79 RC-1 2013.4 1511.4 1.36 21.811.84 RG-603 5193 1568 0.99 21.1 0.81 RG-601 2847 2279 1.16 13.53 1.14RG-605 3361 1576 0.3 20.99 0.53 RG-606 2303 804 0.34 41.29 0.91 RG-6234134 10519 3.98 3.18 0.56 RG-621 4759.45 6231.79 1.71 5.33 0.52 RM-12009.24 1328.09 0.49 24.89 0.91 RZ-405 3040.6 7007.7 4.05 4.74 0.69

In another experiment, Sprague Dawley rats were dosed per os using anormal saline formulation containing 10 mg/kg of the compoundsidentified in the table below (except for the first four compounds thatwere delivered in 5% NMP, 5% Solutol® HS and 90% normal salineformulation). Plasma, brain, and CSF samples were analyzed at varioustime points over a 24 hour period. The table below summarizes theresults of the oral pharmacokinetics.

AUC_(last) CSF Brain T_(max) C_(max) (hr*ng/ C_(max) C_(max) Compound(hr) (ng/mL) mL) (ng/mL) (ng/mL) % F RE-1 0.25 495.17 272.7 86.1 22 40RA-1 0.25 592 324.2 102.5 203.6 28 RB-1 1.17 825.1 3288 27.4 40.2 52RC-1 1.67 990.2 3668.7 20.8 27.6 49 RG-603 1 311 897 — — 11 RG-601 0.833989 9509 1151 1447 83 RG-605 0.25 6478 6370 1211 733 81 RG-606 0.252812 1933 1077 612 48 RG-623 0.42 10891 42553 4727 4317 81 RG-621 0.5812037.25 29103.5 3654.37 1977.29 93 RW-1 1 4074 NR 853 NR NR RM-1 0.254309.99 5008.61 1415 2763 75 RZ-405 0.5 10783 29521 3157 2209 84

Example 8

A non-clinical in vivo pharmacology study (Porsolt assay) was performedto measure antidepressant-like effects. A negative control (0.5% sodiumcarboxymethyl cellulose in 0.9% sterile saline vehicle) and a positivecontrol (fluoxetine) are shown for comparison against test compound. Thestudy allowed for the evaluation of the effects of each compound on thePorsolt forced swim test as assessed by the rats' response (reducedfloating time) during a 5-minute swimming test.

Male 2-3 month old Sprague Dawley rats were used (Harlan, Indianapolis,IN). Rats were housed in Lucite cages with aspen wood chip bedding,maintained on a 12:12 light:dark cycle (lights on at 5 AM), and given adlibitum access to Purina lab chow (USA) and tap water throughout thestudy.

The Porsolt forced swim test adapted for use in rats was performed asdescribed by Burgdorf et al., (The long-lasting antidepressant effectsof rapastinel (GLYX-13) are associated with a metaplasticity process inthe medial prefrontal cortex and hippocampus. Neuroscience 308:202-211,2015). Animals were placed in a 46 cm tall×20 cm in diameter clear glasstube filled to 30 cm with tap water (23±1° C.) for 15 min on the firstday (habituation) and 5 min on the subsequent test day. Positive controlfluoxetine was dosed 3 times (24 h, 5 h and 1 h) prior to testing.Animals were tested 1 h or 24 h post-dosing with the test compounds orvehicle. Animals received a 15 min habituation session 1 day before the5 min test. A subset of compounds tested at 1 h post-dosing wereretested at 1 wk post-dosing in the same sets of animals. Water waschanged after every other animal. Animals were videotaped, and floatingtime as defined as the minimal amount of effort required to keep theanimals head above water was scored offline by a blinded experimenterwith high inter-rater reliability (Pearson's r>0.9).

The results for test compounds are shown in the table below. Eachcompound tested at dose level shown. Significance vs. vehicle group foreach experiment is marked. A compound marked “Yes” was found to bestatistically significant (p<=0.05) from vehicle at dose level shown. Acompound marked “No” was not statistically significant from vehicle.Data was averaged for test compound and vehicle groups (N approximately8 per group) and the percent reduction in floating for group treatedwith test compound relative to group treated with vehicle is shown.

1 h post-dose 24 h post-dose 1 wk post-dose % % % reduction Dosereduction Dose reduction Dose Significance in float (0.1 Significance infloat (0.1 Significance in float Compound (mg/kg) vs. vehicle timemg/kg) vs. vehicle time mg/kg) vs. vehicle time Fluoxetine 20   Yes  54% NA NA NA NA NA NA RG-601 0.1 Yes 82.7% NR NR NR 0.1 Yes 34.4%RG-602 0.1 Yes 71.1% NR NR NR 0.1 Yes 55.5% RG-623 0.1 Yes 60.0% 0.1 Yes52.9% NR NR NR RZ-405 0.1 Yes 78.9% 0.1 Yes 42.7% NR NR NR

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications,websites, and other references cited herein are hereby expresslyincorporated herein in their entireties by reference.

1. A compound represented by:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof,wherein: X is NR¹ or CR²R²; Y is NR¹ or CR²R², wherein one of X or Y isNR¹; R¹ is selected from the group consisting of H, C₁-C₆alkyl, phenyl,—C(O)—C₁-C₆alkyl, and —C(O)—O—C₁-C₆ alkyl; q is 0 or 1; r is 1 or 2; R⁷is independently selected from the group consisting of H, —C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, and halogen; R⁹ is independently selected from thegroup consisting of H, —C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, and halogen,or one R⁷ and one R⁹ taken together with the adjacent carbons to whichthey are attached form a 3-membered carbocyclic ring which can beoptionally substituted by one or two substituents independently selectedfrom the group consisting of halogen, hydroxyl, —C₁-C₃alkyl,—C₁-C₃alkoxy, —C(O)NR^(a)R^(b), and —NR^(a)R^(b); R² is independentlyselected for each occurrence from the group consisting of H, C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; R⁵ is independentlyselected for each occurrence from the group consisting of H, C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; R⁶ represents one or twooptional substitutions each on one or more available ring carbons, andis independently selected for each occurrence from the group consistingof C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; w is 0,1, or 2; R³ is selected from the group consisting of H, phenyl, C₁-C₆alkyl, —C(O)R³¹ and —C(O)OR³²; R³¹ and R³² are each independentlyselected from the group consisting of H, C₁-C₆alkyl, —C₃-C₆cycloalkyl,and phenyl; and R^(a) and R^(b) are each independently for eachoccurrence selected from the group consisting of H, phenyl, andC₁-C₃alkyl, or R^(a) and R^(b) taken together with the nitrogen to whichthey are attached form a 4-6 membered heterocyclic ring; wherein anyaforementioned C₁-C₆ alkyl, independently for each occurrence, isoptionally substituted by one, two or three substituents eachindependently selected from —C(O)NR^(a)R^(b), —NR^(a)R^(b), hydroxyl,S(O)_(w)—C₁-C₃alkyl, SH, phenyl and halogen, and any aforementionedphenyl, independently for each occurrence, is optionally substituted byone, two or three substituents each independently selected from—C(O)—C₁-C₃alkyl, hydroxyl, —C(O)— C₁-C₃alkyl, methyl, CF₃ and halogen.2. The compound of claim 1, wherein q is
 1. 3. The compound of claim 1,wherein q is
 0. 4. The compound of claim 1, wherein q is 0 and r is 2.5. The compound of claim 1, wherein X is NR¹ and Y is CR²R².
 6. Acompound represented by:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof,wherein: R¹ is selected from the group consisting of H, C₁-C₆alkyl,phenyl, —C(O)—C₁-C₆alkyl, and —C(O)—O—C₁-C₆ alkyl; R⁷ is independentlyselected from the group consisting of H, —C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, and halogen; R⁹ is independently selected from thegroup consisting of H, —C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, and halogen,or one R⁷ and one R⁹ taken together with the adjacent carbons to whichthey are attached form a 3-membered carbocyclic ring which can beoptionally substituted by one or two substituents independently selectedfrom the group consisting of halogen, hydroxyl, —C₁-C₃alkyl,—C₁-C₃alkoxy, —C(O)NR^(a)R^(b), and —NR^(a)R^(b); R² is independentlyselected for each occurrence from the group consisting of H, C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; R⁵ is independentlyselected for each occurrence from the group consisting of H, C₁-C₆alkyl,—S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; R⁶ represents one or twooptional substitutions each on one or more available ring carbons, andis independently selected for each occurrence from the group consistingof C₁-C₆alkyl, —S(O)_(w)—C₁-C₃alkyl, —NR^(a)R^(b) and halogen; w is 0,1, or 2; R³ is selected from the group consisting of H, phenyl, C₁-C₆alkyl, —C(O)R³¹ and —C(O)OR³²; R³¹ and R³² are each independentlyselected from the group consisting of H, C₁-C₆alkyl, —C₃-C₆cycloalkyl,and phenyl; and R^(a) and R^(b) are each independently for eachoccurrence selected from the group consisting of H, phenyl, andC₁-C₃alkyl, or R^(a) and R^(b) taken together with the nitrogen to whichthey are attached form a 4-6 membered heterocyclic ring; wherein anyaforementioned C₁-C₆ alkyl, independently for each occurrence, isoptionally substituted by one, two or three substituents eachindependently selected from —C(O)NR^(a)R^(b), —NR^(a)R^(b), hydroxyl,S(O)_(w)—C₁-C₃alkyl, SH, phenyl and halogen, and any aforementionedphenyl, independently for each occurrence, is optionally substituted byone, two or three substituents each independently selected from—C(O)—C₁-C₃alkyl, hydroxyl, —C(O)— C₁-C₃alkyl, methyl, CF₃ and halogen.7. The compound of claim 6, wherein R¹ is C(O)—O—C₁-C₆ alkyl.
 8. Thecompound of claim 6, wherein R¹ is —C(O)—C₁-C₆alkyl.
 9. The compound ofclaim 6, wherein R¹ is C₁-C₆alkyl.
 10. The compound of claim 6, whereinR¹ is H.
 11. The compound of claim 8, wherein R¹ is selected from thegroup consisting of:

wherein R^(a) and R^(b) are each independently selected for eachoccurrence from the group consisting of hydrogen and —C₁-C₃alkyl. 12.The compound of claim 9, wherein R¹ is


13. The compound of claim 7, wherein R¹ is tert-butyloxycarbonyl. 14.The compound of claim 6, wherein R¹ is


15. The compound of claim 6, wherein R³ is H.
 16. The compound of claim6, wherein R³ is selected from the group consisting of:

wherein R^(a) and R^(b) are each independently selected for eachoccurrence from the group consisting of hydrogen and —C₁-C₃alkyl. 17-23.(canceled)
 24. A compound selected from the compounds delineated in thetable of Example 2 and the table of Example 4, or a pharmaceuticallyacceptable salt or a stereoisomer thereof.
 25. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable excipient.
 26. (canceled)
 27. A method of treatingdepression, Alzheimer's disease, attention deficit disorder,schizophrenia, or anxiety, in a patient in need thereof, the methodcomprising administering to the patient a therapeutically effectiveamount of the compound of claim
 1. 28-31. (canceled)